Korean J Transplant.  2019 Dec;33(4):74-82. 10.4285/jkstn.2019.33.4.74.

Macrophages in xenotransplantation

Affiliations
  • 1Department of Life Science, Gachon University, Seongnam, Korea. jykim85@gachon.ac.kr

Abstract

Xenotransplantation refers to organ transplantation across species. Immune rejection of xenografts is stronger and faster than that of allografts because of significant molecular differences between species. Recent studies have revealed the involvement of macrophages in xenograft and allograft rejections. Macrophages have been shown to play a critical role in inflammation, coagulation, and phagocytosis in xenograft rejection. This review presents a recent understanding of the role of macrophages in xenograft rejection and possible strategies to control macrophage-mediated xenograft rejection.

Keyword

Xenotransplantation; Macrophages; Inflammation; Coagulation

MeSH Terms

Allografts
Heterografts
Inflammation
Macrophages*
Organ Transplantation
Phagocytosis
Transplantation, Heterologous*
Transplants

Figure

  • Fig. 1 (A–C) Central role of activated macrophages in inflammation, coagulation, phagocytosis, and antigen presentation [31]. TNF, tumor necros; IL, interleukin; MCP-1, monocyte chemoattractant protein 1; DAMP, damage-associated molecular pattern; TLR, Toll-like receptor; TF, tissue factor; PLT, platelet; VWF, von Willebrand factor; PF4, platelet factor 4; TM, thrombomodulin; PAR, protease-activated receptor; ICAM-1, intercellular adhesion molecule-1; VCAM-1, vascular cell adhesion molecule-1; SIRPα, signal regulatory protein α.

  • Fig. 2 Possible cross-talk between macrophages, hepatocytes, and vascular endothelial cells through the production of interleukin (IL)-6, monocyte chemoattractant protein 1 (MCP-1), and C-reactive protein (CRP) in inflammatory responses and coagulation in pig-to-baboon organ transplantation. TF, tissue factor.


Reference

1. Samstein B, Platt JL. Physiologic and immunologic hurdles to xenotransplantation. J Am Soc Nephrol. 2001; 12:182–193.
Article
2. Galili U. The alpha-gal epitope and the anti-Gal antibody in xenotransplantation and in cancer immunotherapy. Immunol Cell Biol. 2005; 83:674–686.
Article
3. Cooper DK, Ekser B, Tector AJ. Immunobiological barriers to xenotransplantation. Int J Surg. 2015; 23(Pt B):211–216.
Article
4. Denner J. Xenotransplantation-progress and problems: a review. J Transplant Technol Res. 2014; 4:1000133.
Article
5. Zecher D, van Rooijen N, Rothstein DM, Shlomchik WD, Lakkis FG. An innate response to allogeneic nonself mediated by monocytes. J Immunol. 2009; 183:7810–7816.
Article
6. Oberbarnscheidt MH, Zeng Q, Li Q, Dai H, Williams AL, Shlomchik WD, et al. Non-self recognition by monocytes initiates allograft rejection. J Clin Invest. 2014; 124:3579–3589.
Article
7. Liu W, Xiao X, Demirci G, Madsen J, Li XC. Innate NK cells and macrophages recognize and reject allogeneic nonself in vivo via different mechanisms. J Immunol. 2012; 188:2703–2711.
Article
8. Matheson PJ, Dittmer ID, Beaumont BW, Merrilees MJ, Pilmore HL. The macrophage is the predominant inflammatory cell in renal allograft intimal arteritis. Transplantation. 2005; 79:1658–1662.
Article
9. Xu L, Collins J, Drachenberg C, Kukuruga D, Burke A. Increased macrophage density of cardiac allograft biopsies is associated with antibody-mediated rejection and alloantibodies to HLA antigens. Clin Transplant. 2014; 28:554–560.
Article
10. Bergler T, Jung B, Bourier F, Kühne L, Banas MC, Rümmele P, et al. Infiltration of macrophages correlates with severity of allograft rejection and outcome in human kidney transplantation. PLoS One. 2016; 11:e0156900.
Article
11. Bräsen JH, Khalifa A, Schmitz J, Dai W, Einecke G, Schwarz A, et al. Macrophage density in early surveillance biopsies predicts future renal transplant function. Kidney Int. 2017; 92:479–489.
Article
12. Matzinger P. Tolerance, danger, and the extended family. Annu Rev Immunol. 1994; 12:991–1045.
Article
13. Wu H, Chen G, Wyburn KR, Yin J, Bertolino P, Eris JM, et al. TLR4 activation mediates kidney ischemia/reperfusion injury. J Clin Invest. 2007; 117:2847–2859.
Article
14. Kaczorowski DJ, Nakao A, Vallabhaneni R, Mollen KP, Sugimoto R, Kohmoto J, et al. Mechanisms of Toll-like receptor 4 (TLR4)-mediated inflammation after cold ischemia/reperfusion in the heart. Transplantation. 2009; 87:1455–1463.
Article
15. Yang Z, Deng Y, Su D, Tian J, Gao Y, He Z, et al. TLR4 as receptor for HMGB1-mediated acute lung injury after liver ischemia/reperfusion injury. Lab Invest. 2013; 93:792–800.
Article
16. Weber DJ, Gracon AS, Ripsch MS, Fisher AJ, Cheon BM, Pandya PH, et al. The HMGB1-RAGE axis mediates traumatic brain injury-induced pulmonary dysfunction in lung transplantation. Sci Transl Med. 2014; 6:252ra124.
Article
17. Hu Q, Wood CR, Cimen S, Venkatachalam AB, Alwayn IP. Mitochondrial damage-associated molecular patterns (MTDs) are released during hepatic ischemia reperfusion and induce inflammatory responses. PLoS One. 2015; 10:e0140105.
Article
18. De Vlaminck I, Martin L, Kertesz M, Patel K, Kowarsky M, Strehl C, et al. Noninvasive monitoring of infection and rejection after lung transplantation. Proc Natl Acad Sci U S A. 2015; 112:13336–13341.
Article
19. Gielis EM, Ledeganck KJ, De Winter BY, Del Favero J, Bosmans JL, Claas FH, et al. Cell-free DNA: an upcoming biomarker in transplantation. Am J Transplant. 2015; 15:2541–2551.
Article
20. Baba HA, Schmid KW, Schmid C, Blasius S, Heinecke A, Kerber S, et al. Possible relationship between heat shock protein 70, cardiac hemodynamics, and survival in the early period after heart transplantation. Transplantation. 1998; 65:799–804.
Article
21. Schimke I, Lutsch G, Schernes U, Kruse I, Dübel HP, Pregla R, et al. Increased level of HSP27 but not of HSP72 in human heart allografts in relation to acute rejection. Transplantation. 2000; 70:1694–1697.
Article
22. Sarri S, Shaw SM, Gieschen-Krische MA, Archer L, Yonan N, Fildes JE. Myocardial heat shock protein 60 expression is upregulated following acute cardiac rejection. Transpl Immunol. 2009; 21:140–142.
Article
23. Maehana T, Tanaka T, Kitamura H, Fukuzawa N, Ishida H, Harada H, et al. Heat shock protein 90α is a potential serological biomarker of acute rejection after renal transplantation. PLoS One. 2016; 11:e0162942.
Article
24. Esmon CT. Molecular circuits in thrombosis and inflammation. Thromb Haemost. 2013; 109:416–420.
Article
25. Idzko M, Ferrari D, Eltzschig HK. Nucleotide signalling during inflammation. Nature. 2014; 509:310–317.
Article
26. Yoshida O, Dou L, Kimura S, Yokota S, Isse K, Robson SC, et al. CD39 deficiency in murine liver allografts promotes inflammatory injury and immune-mediated rejection. Transpl Immunol. 2015; 32:76–83.
Article
27. Jennewein C, Paulus P, Zacharowski K. Linking inflammation and coagulation: novel drug targets to treat organ ischemia. Curr Opin Anaesthesiol. 2011; 24:375–380.
28. Osterud B, Olsen JO, Bjørklid E. What is blood borne tissue factor? Thromb Res. 2009; 124:640–641.
Article
29. Ezzelarab M, Garcia B, Azimzadeh A, Sun H, Lin CC, Hara H, et al. The innate immune response and activation of coagulation in alpha1,3-galactosyltransferase gene-knockout xenograft recipients. Transplantation. 2009; 87:805–812.
Article
30. Lin CC, Ezzelarab M, Shapiro R, Ekser B, Long C, Hara H, et al. Recipient tissue factor expression is associated with consumptive coagulopathy in pig-to-primate kidney xenotransplantation. Am J Transplant. 2010; 10:1556–1568.
Article
31. Foley JH, Conway EM. Cross talk pathways between coagulation and inflammation. Circ Res. 2016; 118:1392–1408.
Article
32. Gao H, Liu L, Zhao Y, Hara H, Chen P, Xu J, et al. Human IL-6, IL-17, IL-1β, and TNF-α differently regulate the expression of pro-inflammatory related genes, tissue factor, and swine leukocyte antigen class I in porcine aortic endothelial cells. Xenotransplantation. 2017; 24:e12291.
Article
33. Iwase H, Ekser B, Zhou H, Dons EM, Cooper DK, Ezzelarab MB. Platelet aggregation in humans and nonhuman primates: relevance to xenotransplantation. Xenotransplantation. 2012; 19:233–243.
Article
34. Ezzelarab MB, Cooper DK. Systemic inflammation in xenograft recipients (SIXR): a new paradigm in pig- to-primate xenotransplantation? Int J Surg. 2015; 23(Pt B):301–305.
Article
35. Ezzelarab MB, Ekser B, Azimzadeh A, Lin CC, Zhao Y, Rodriguez R, et al. Systemic inflammation in xenograft recipients precedes activation of coagulation. Xenotransplantation. 2015; 22:32–47.
Article
36. Iwase H, Ekser B, Zhou H, Liu H, Satyananda V, Humar R, et al. Further evidence for sustained systemic inflammation in xenograft recipients (SIXR). Xenotransplantation. 2015; 22:399–405.
Article
37. Dai H, Friday AJ, Abou-Daya KI, Williams AL, Mortin-Toth S, Nicotra ML, et al. Donor SIRPa polymorphism modulates the innate immune response to allogeneic grafts. Sci Immunol. 2017; 2:eaam6202.
Article
38. Ide K, Wang H, Tahara H, Liu J, Wang X, Asahara T, et al. Role for CD47-SIRPalpha signaling in xenograft rejection by macrophages. Proc Natl Acad Sci U S A. 2007; 104:5062–5066.
39. Todd JL, Palmer SM. Danger signals in regulating the immune response to solid organ transplantation. J Clin Invest. 2017; 127:2464–2472.
Article
40. Roh JS, Sohn DH. Damage-associated molecular patterns in inflammatory diseases. Immune Netw. 2018; 18:e27.
Article
41. Tena A, Kurtz J, Leonard DA, Dobrinsky JR, Terlouw SL, Mtango N, et al. Transgenic expression of human CD47 markedly increases engraftment in a murine model of pig-to-human hematopoietic cell transplantation. Am J Transplant. 2014; 14:2713–2722.
Article
42. Hancock WW, Thomson NM, Atkins RC. Composition of interstitial cellular infiltrate identified by monoclonal antibodies in renal biopsies of rejecting human renal allografts. Transplantation. 1983; 35:458–463.
Article
43. Candinas D, Lesnikoski BA, Robson SC, Miyatake T, Scesney SM, Marsh HC Jr, et al. Effect of repetitive high-dose treatment with soluble complement receptor type 1 and cobra venom factor on discordant xenograft survival. Transplantation. 1996; 62:336–342.
Article
44. Lin Y, Vandeputte M, Waer M. Natural killer cell- and macrophage-mediated rejection of concordant xenografts in the absence of T and B cell responses. J Immunol. 1997; 158:5658–5667.
45. Samy KP, Davis RP, Gao Q, Martin BM, Song M, Cano J, et al. Early barriers to neonatal porcine islet engraftment in a dual transplant model. Am J Transplant. 2018; 18:998–1006.
Article
46. Ehrnfelt C, Kumagai-Braesch M, Uzunel M, Holgersson J. Adult porcine islets produce MCP-1 and recruit human monocytes in vitro. Xenotransplantation. 2004; 11:184–194.
Article
47. An HJ, Jang JW, Bae SH, Choi JY, Yoon SK, Lee MA, et al. Serum C-reactive protein is a useful biomarker for predicting outcomes after liver transplantation in patients with hepatocellular carcinoma. Liver Transpl. 2012; 18:1406–1414.
Article
48. Boras E, Slevin M, Alexander MY, Aljohi A, Gilmore W, Ashworth J, et al. Monomeric C-reactive protein and Notch-3 co-operatively increase angiogenesis through PI3K signalling pathway. Cytokine. 2014; 69:165–179.
Article
49. Han KH, Hong KH, Park JH, Ko J, Kang DH, Choi KJ, et al. C-reactive protein promotes monocyte chemoattractant protein-1—mediated chemotaxis through upregulating CC chemokine receptor 2 expression in human monocytes. Circulation. 2004; 109:2566–2571.
Article
50. Kruithof EK, Mestries JC, Gascon MP, Ythier A. The coagulation and fibrinolytic responses of baboons after in vivo thrombin generation: effect of interleukin 6. Thromb Haemost. 1997; 77:905–910.
51. Hage FG, Szalai AJ. C-reactive protein gene polymorphisms, C-reactive protein blood levels, and cardiovascular disease risk. J Am Coll Cardiol. 2007; 50:1115–1122.
Article
52. Li J, Hara H, Wang Y, Esmon C, Cooper DK, Iwase H. Evidence for the important role of inflammation in xenotransplantation. J Inflamm (Lond). 2019; 16:10.
Article
53. Cooper DK, Dou KF, Tao KS, Yang ZX, Tector AJ, Ekser B. Pig liver xenotransplantation: a review of progress toward the clinic. Transplantation. 2016; 100:2039–2047.
54. Engel D, Seijkens T, Poggi M, Sanati M, Thevissen L, Beckers L, et al. The immunobiology of CD154-CD40-TRAF interactions in atherosclerosis. Semin Immunol. 2009; 21:308–312.
Article
55. Li T, Lee W, Hara H, Long C, Ezzelarab M, Ayares D, et al. An investigation of extracellular histones in pig-to-baboon organ xenotransplantation. Transplantation. 2017; 101:2330–2339.
Article
56. Iwase H, Liu H, Li T, Zhang Z, Gao B, Hara H, et al. Therapeutic regulation of systemic inflammation in xenograft recipients. Xenotransplantation. 2017; 24:e12296.
Article
57. Chung H, Hong SJ, Choi SW, Koo JY, Kim M, Kim HJ, et al. High mobility group box 1 secretion blockade results in the reduction of early pancreatic islet graft loss. Biochem Biophys Res Commun. 2019; 514:1081–1086.
Article
58. Vergani A, Tezza S, D'Addio F, Fotino C, Liu K, Niewczas M, et al. Long-term heart transplant survival by targeting the ionotropic purinergic receptor P2X7. Circulation. 2013; 127:463–475.
Article
59. Wu H, Steenstra R, de Boer EC, Zhao CY, Ma J, van der Stelt JM, et al. Preconditioning with recombinant high-mobility group box 1 protein protects the kidney against ischemia-reperfusion injury in mice. Kidney Int. 2014; 85:824–832.
Article
60. Izuishi K, Tsung A, Jeyabalan G, Critchlow ND, Li J, Tracey KJ, et al. Cutting edge: high-mobility group box 1 preconditioning protects against liver ischemia-reperfusion injury. J Immunol. 2006; 176:7154–7158.
Article
61. Seemampillai B, Germack R, Felkin LE, McCormack A, Rose ML. Heat shock protein-27 delays acute rejection after cardiac transplantation: an experimental model. Transplantation. 2014; 98:29–38.
Article
62. Qi F, Adair A, Ferenbach D, Vass DG, Mylonas KJ, Kipari T, et al. Depletion of cells of monocyte lineage prevents loss of renal microvasculature in murine kidney transplantation. Transplantation. 2008; 86:1267–1274.
Article
63. Hutchinson JA, Riquelme P, Sawitzki B, Tomiuk S, Miqueu P, Zuhayra M, et al. Cutting edge: immunological consequences and trafficking of human regulatory macrophages administered to renal transplant recipients. J Immunol. 2011; 187:2072–2078.
Article
64. Riquelme P, Haarer J, Kammler A, Walter L, Tomiuk S, Ahrens N, et al. TIGIT(+) iTregs elicited by human regulatory macrophages control T cell immunity. Nat Commun. 2018; 9:2858.
Article
65. Hutchinson JA, Brem-Exner BG, Riquelme P, Roelen D, Schulze M, Ivens K, et al. A cell-based approach to the minimization of immunosuppression in renal transplantation. Transpl Int. 2008; 21:742–754.
Article
66. Netea MG, Latz E, Mills KH, O'Neill LA. Innate immune memory: a paradigm shift in understanding host defense. Nat Immunol. 2015; 16:675–679.
Article
Full Text Links
  • KJT
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr